Cabozantinib and Pembrolizumab for Advanced Metastatic Melanoma

NCT03957551 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: 201904712
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

The study aims to evaluate the safety and preliminary efficacy of the combination of cabozantinib and pembrolizumab in advanced melanoma

Conditions

Advanced Metastatic Melanoma

Outcome Measures

Primary Outcomes (2)

• Phase I: Number of Participants With a Dose Limiting Toxicity (DLT) Using CTCAE, Version 4.03

  All adverse events (AEs) will be considered in DLT assessment unless an event is clearly unrelated to trial treatment. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 will be used.

  Up to 21 days

• Phase II: Overall Response Rate

  The overall response rate (ORR) is the percentage of patients with a complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1). A complete response (CR) is the disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to \<10 mm, and partial response (PR) is a \>=30% decrease in the sum of the longest diameter of target lesions.

  Initiation of treatment up to 2 years

Secondary Outcomes (3)

• Disease Control Rate

  Initiation of treatment up to 2 years

• Progression-Free Survival

  Initiation of treatment up to 2 years

• Overall Survival at 2 Years

  Initiation of treatment up to 2 years

Study Arms (1)

Cabozantinib and pembrolizumab

EXPERIMENTAL

Cabozantinib will be administered in the tablet form, at three dose levels: 40, 20 and 60 mg per day. Pembrolizumab will be administered as an intravenous infusion at a fixed dose of 200 mg once every 3 weeks.

Drug: Cabozantinib; Drug: Pembrolizumab

Interventions

Cabozantinib DRUG

Cabozantinib is an oral small molecule potent inhibitor of pro-invasive receptor tyrosine kinases (RTKs). Cabozantinib will be administered in the tablet form, at three dose levels: 40, 20 and 60 mg per day, in combination with pembrolizumab. The drug is taken continuously for 21 days or 3 weeks. This period of time is defined as one treatment cycle.

Also known as: XL184, COMETRIQ™, Cabometyx®

Cabozantinib and pembrolizumab

Pembrolizumab DRUG

Pembrolizumab is a humanized antibody which will be administered as an intravenous infusion at a fixed dose of 200 mg once every 3 weeks in combination with cabozantinib.

Also known as: Keytruda

Cabozantinib and pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A patient must meet all of the following criteria to be eligible for enrollment (defined as receiving the first trial treatment) in the trial:
• Histologically or cytologically confirmed unresectable in-transit (stage IIIc) or metastatic (stage IV) melanoma.
• Must have at least 1 lesion that qualifies as a measurable (target) lesion per RECIST v1.1
• Subjects must be willing to have blood draws for future biomarker testing as outlined in Section 11.9 of the protocol.
• The subject has an ECOG performance score of \</= 2 However; the phase 1b part will include only ECOG performance of 0-1 and life expectancy of \>12 weeks
• Aged 18 years and older.
• The subject should not have received any treatment for advanced melanoma, EXCEPT, BRAF and/or MEK inhibitor. (2 week washout)
• The subjects who have received adjuvant therapy including anti- PD-1 can be included in the study, if the last dose of the adjuvant treatment was \>/= 6 months prior to developing metastatic relapse.
• The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.
• Female patients of childbearing potential, must have a negative urine or serum pregnancy test within 72 hours prior to taking the first dose of study medication, if.
• If the urine test is positive or cannot be confirmed as negative then a serum test is required which must be negative for the patient to enroll.
• Women of childbearing potential (WOCBP) must be willing to use 2 medically acceptable methods of contraceptive from Day 1 through 120 days after the last dose of trial treatment. The 2 medically acceptable birth control methods can be either 2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy. The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), copper intrauterine device, sponge, or spermicide as per local regulations or guidelines. Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents).
• Male patients of reproductive potential must agree to use an adequate method of contraception from Day 1 through 120 days after the last dose of trial treatment. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
• Able to swallow pills.
• The subject must have recovered to baseline or \< Grade 1 CTCAE v 4 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and /or stable on supportive therapy.

You may not qualify if:

• A patient meeting any of the following criteria is not eligible to participate in this study:
• Subject had prior treatment with any anti-PD-1, anti-PD-L1, or anti- PD-L2 agent for the treatment of advanced melanoma (although prior use in adjuvant setting is allowed if the last dose \> 6 months prior developing metastatic disease).
• Subjects with diagnosis of ocular and mucosal melanoma
• Subject had prior cabozantinib for any indication.
• Subject who received any small molecule tyrosine kinase inhibitor within 2 weeks before first dose of study treatment.
• Subject who has had chemotherapy, radioactive, or biological cancer therapy within four weeks prior to the first dose of study drug, or who has not recovered to CTCAE Grade 1 or better from the AEs due to cancer therapeutics administered more than four weeks earlier.
• Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug. (A patient in the Survival Follow up phase of an investigational agent where no further treatment is expected is eligible).Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study.
• Patient is on any systemic corticosteroid therapy (more than 10 mg daily of prednisone or equivalent) within one week before the planned date for first dose of randomized treatment or on any other form of immunosuppressive medication.
• Patient has a history of a malignancy (other than the disease under treatment in the study) within 2 years prior to first study drug administration. This should exclude adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers. Shorter intervals can be considered after discussion with Sponsor.
• Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by MRI for at least four weeks prior to the first dose of study drug), have no evidence of new or enlarging brain metastases, neurologically asymptomatic and are off systemic steroids for at least two weeks.
• Patient previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody or small molecule tyrosine kinase inhibitor.
• Patient has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement will not be excluded from the study.
• Patient has an active infection requiring systemic therapy.
• Patient has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

Sponsors & Collaborators

• John Rieth: lead
• Exelixis: collaborator
• University of Iowa: collaborator

Study Sites (1)

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

MeSH Terms

Interventions

cabozantinib; pembrolizumab

Limitations and Caveats

Study was terminated early due to changes in the treatment of melanoma.

Results Point of Contact

• Title: John Rieth, MD
• Organization: University of Iowa

john-rieth@uiowa.edu

(319) 356-1616

Study Officials

• John Rieth, MD

  University of Iowa

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical Assistant Professor

Model Details: Dose escalation

Study Record Dates

• First Submitted: May 17, 2019
• First Posted: May 21, 2019
• Study Start: August 27, 2019
• Primary Completion: June 10, 2024
• Study Completion: October 17, 2025
• Last Updated: January 29, 2026
• Results First Posted: August 24, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)